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Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

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Related in: MedlinePlus

Survival advantage in tumor-bearing mice treated with modified XS52 cells. Animals were immunized with XS52 cells modified with  Adβgal or AdNull. The experiment is similar to that depicted in Fig. 5,  except that the animals were not killed but were followed for survival.  The data is expressed as percentage of survival as a function of time. Survival for mice which were treated with XS52-Adβgal was significantly  prolonged over the XS52-AdNull control, as determined by log-rank  analysis of the Kaplan-Meier survival curves (P <0.002).
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Figure 6: Survival advantage in tumor-bearing mice treated with modified XS52 cells. Animals were immunized with XS52 cells modified with Adβgal or AdNull. The experiment is similar to that depicted in Fig. 5, except that the animals were not killed but were followed for survival. The data is expressed as percentage of survival as a function of time. Survival for mice which were treated with XS52-Adβgal was significantly prolonged over the XS52-AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.002).

Mentions: In cancer treatment, any observed treatment response becomes even more meaningful if it translates into a survival advantage. To evaluate if the reduction in the number of lung metastases in mice treated with XS52-Adβgal conferred a survival advantage, a group of animals were followed for survival. Tumor-bearing mice that were treated with XS52-Adβgal lived significantly longer than the animals in the negative control groups (P <0.002, Fig. 6). Consistent with the observation in the prevention experiment, XS52-Adβgal treatment did not suppress preestablished non–βgal-expressing CT26.WT tumors (not shown), again suggesting that the therapeutic effect is antigen (βgal)-specific (P >0.2). Further, lysed XS52-Adβgal cells did not confer a survival advantage as compared to untreated mice or mice treated with XS52-AdNull (P >0.8; not shown).


Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Survival advantage in tumor-bearing mice treated with modified XS52 cells. Animals were immunized with XS52 cells modified with  Adβgal or AdNull. The experiment is similar to that depicted in Fig. 5,  except that the animals were not killed but were followed for survival.  The data is expressed as percentage of survival as a function of time. Survival for mice which were treated with XS52-Adβgal was significantly  prolonged over the XS52-AdNull control, as determined by log-rank  analysis of the Kaplan-Meier survival curves (P <0.002).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199096&req=5

Figure 6: Survival advantage in tumor-bearing mice treated with modified XS52 cells. Animals were immunized with XS52 cells modified with Adβgal or AdNull. The experiment is similar to that depicted in Fig. 5, except that the animals were not killed but were followed for survival. The data is expressed as percentage of survival as a function of time. Survival for mice which were treated with XS52-Adβgal was significantly prolonged over the XS52-AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.002).
Mentions: In cancer treatment, any observed treatment response becomes even more meaningful if it translates into a survival advantage. To evaluate if the reduction in the number of lung metastases in mice treated with XS52-Adβgal conferred a survival advantage, a group of animals were followed for survival. Tumor-bearing mice that were treated with XS52-Adβgal lived significantly longer than the animals in the negative control groups (P <0.002, Fig. 6). Consistent with the observation in the prevention experiment, XS52-Adβgal treatment did not suppress preestablished non–βgal-expressing CT26.WT tumors (not shown), again suggesting that the therapeutic effect is antigen (βgal)-specific (P >0.2). Further, lysed XS52-Adβgal cells did not confer a survival advantage as compared to untreated mice or mice treated with XS52-AdNull (P >0.8; not shown).

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Show MeSH
Related in: MedlinePlus